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研究生:莊晴
研究生(外文):Ching Chuang
論文名稱:3×Tg-AD小鼠大氣微粒暴露對阿茲海默症病程影響先驅研究
論文名稱(外文):Ambient particles exposure and progress of Alzheimer''s disease in 3xTg-AD mice: a pilot study
指導教授:鄭尊仁鄭尊仁引用關係
口試日期:2017-07-27
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:56
中文關鍵詞:大氣細懸浮微粒阿茲海默症類澱粉蛋白斑塊神經纖維纏結中樞神經莫氏水迷氧化壓力
外文關鍵詞:mbient particlesamyloid plaqueneurofibrillary tangles (NFTs)CNSMorris water mazeoxidative stress
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過去研究顯示,PM對人體會有不良健康效應,暴露微粒與心血管、肺部疾病的發生率及死亡率相關。空氣微粒可能直接進到腦部,或經由周邊組織發炎,再藉由神經發炎、氧化壓力等對中樞神經系統(central nervous system, CNS)造成影響,PM可能影響的中樞神經系統疾病包括阿茲海默症(Alzheimer''s disease,AD)及帕金森氏症(Parkinson’s disease)等神經退化疾病。阿茲海默症為漸進式神經退化性疾病,是最常見的失智症。這種疾病在神經病理學有兩種主要的病徵:由乙型類澱粉蛋白(amyloid-beta, Aβ)沉積所形成的類澱粉蛋白斑塊(amyloid plaque),以及由過度磷酸化滔蛋白(Tau protein)聚集而成的神經纖維糾結(Neurofibrillary Tangles, NFTs)。
現今暴露大氣微粒對阿茲海默症的影響較少毒理研究,因此本研究將利用動物實驗,並著重於小鼠暴露大氣微粒對於阿茲海默症病徵及認知障礙的影響。實驗動物為阿茲海默症基因轉殖動物模式—3×Tg-AD 小鼠,為第一種能夠在阿茲海默症相關腦區同時發展出類澱粉蛋白斑塊及神經纖維纏結病徵之小鼠品系,此種小鼠形成之阿茲海默症病徵與人類相似。17周大的3×Tg-AD 隨機分為控制組(n=5)及暴露組(n=6)進行12周的全身性呼吸暴露,使用臺北空氣污染暴露系統(Taipei Air Pollution Exposure System for Health, TAPES)系統進行暴露,此系統可將外界大氣及微粒抽進暴露腔並提供非濃縮大氣微粒,暴露後進行莫氏水迷津後測,並測試腦中Aβ、磷酸化Tau蛋白及氧化、硝化壓力指標8-OHdG及8-NO2Gua。
本研究小鼠暴露期間PM2.5平均質量濃度為7.6 μg/m3。行為實驗結果顯示亞慢性暴露大氣微粒沒有造成3×Tg-AD小鼠空間學習及記憶功能受損。8-OHdG、8-NO2Gua及Aβ42於海馬迴、小腦、大腦皮質各腦區皆無顯著差異,且多低於偵測極限。組織免疫染色結果顯示Aβ1-16未偵測到訊號,磷酸化Tau蛋白則只有在暴露組其中一隻的大腦皮質偵測到訊號。肺與腦組織切片發現暴露沒有顯著發炎反應。大氣微粒影響阿茲海默症的實際機制與毒性可能需要用年紀較大的3xTg-AD 小鼠進一步探討。
Many studies have shown that particulate matter (PM) may have adverse effects on the human body. PM has been associated with mortality and morbidity of cardiopulmonary diseases. PM may affect the CNS by two pathways, through the direct or peripheral way. In the peripheral way, systemic inflammation induced by PM and transfer inflammatory response to the brain by enhanced neuroinflammation and oxidative stress. PM might contribute to neurodegeneration diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease. Alzheimer’s disease is a progressive neurodegenerative disease and the most common form of dementia, which is pathologically characterized by the amyloid plaque of amyloid-beta (Aβ) , neurofibrillary tangles of hyperphosphorylated tau protein.
However, few toxicology studies explored the association between PM exposure and the progress of AD. The objective of the study is to explore the ambient particulate matter induced pathological lesions and cognitive impairment of Alzheimer''s disease by using 3xTg-AD mice. In the experiment, we use 3xTg-AD mice contain three mutations associated with Alzheimer''s disease. This is the first transgenic model to develop both plaque and tangle pathology in AD- relevant brain regions. The pathology of Alzheimer''s disease is closely mimics the distribution pattern that occurs in human AD brains.
Male 3xTg-AD mice (17 weeks old) were randomly divided into control (filtered air, n=5) and exposure group (ambient PM, n=6) for about 12 weeks whole body inhalation exposure. The ambient air exposure was conducted by using Taipei Air Pollution Exposure System for Health (TAPES). The system can introduce the ambient air outside and provides non-concentrated ambient air. After exposure, Morris water maze post-test were conducted. Aβ, hyperphosphorylated tau protein and oxidative, nitrative stress marker of 8-OHdG and 8-NO2Gua were determined.
The mean mass concentration for exposure ambient PM2.5 was 7.6 μg/m3 during the exposure duration. In Morris water maze test, sub-chronic exposure to ambient PM2.5 may not impair spatial learning and memory in 3xTg-AD mice. 8-OHdG, 8-NO2Gua and Aβ42 were not significantly different between the control and the exposure group in hippocampus, cerebellum and cortex. Most of the 8-OHdG, 8-NO2Gua and Aβ42 levels also below the LOD (Limit of Detection). In the immunohistochemistry stain, Aβ1-16 were not detected and one of the 3xTg-AD mice in the exposure group had more phosphorylated tau protein. We found no significant differences between the control and the exposure group in histopathology of lung and brain. Further study should be conducted to explore the mechanism and toxicity of Alzheimer''s disease induced by PM in the older 3xTg-AD mice.
中文大綱 Ⅰ
Abstract Ⅲ
第一章 前言與研究目的 1
第二章 文獻回顧 2
2.1 空氣微粒健康效應 2
2.2 微粒暴露之中樞神經系統毒性 2
2.3 暴露微粒與阿茲海默症 3
2.4 3×Tg-AD小鼠 4
第三章 材料與方法 6
3.1 實驗流程與架構 6
3.2 實驗動物 7
3.3 大氣懸浮微粒暴露 7
3.3.1 臺北空氣污染暴露系統 8
3.3.2 大氣微粒監測 8
3.4 莫氏水迷津 9
3.5 8-OHdG、8-NO2Gua 分析 10
3.6 腦部Aβ及Tau蛋白 13
3.6.1 乙型類澱粉蛋白測定 13
3.6.2 類澱粉蛋白斑塊免疫組織化學染色 14
3.6.3 神經纖維纏結免疫組織化學染色 15
3.7 組織病理 16
3.8 統計分析 16
第四章 結果 17
4.1 實驗動物體重 17
4.2 PM2.5濃度及元素組成 17
4.3 莫氏水迷津 17
4.4 腦部8-OHdG及8-NO2Gua 18
4.5 腦部Aβ及Tau蛋白 18
4.6 組織病理切片 18
第五章 討論 19
5.1 PM2.5濃度及特性 19
5.2 3×Tg-AD小鼠 19
5.3 微粒效應 21
5.3.1 空間學習及記憶能力 21
5.3.2 8-OHdG及8-NO2Gua 22
5.3.3 腦中Aβ及Tau蛋白 23
5.4 結論與建議 24
第六章 參考文獻 26
1.Brook, R.D., et al., Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation, 2004. 109(21): p. 2655-71.
2.Brook, R.D., et al., Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation, 2010. 121(21): p. 2331-78.
3.Sin, D.D., L.L. Wu, and S.F.P. Man, The relationship between reduced lung function and cardiovascular mortality - A population-based study and a systematic review of the literature. Chest, 2005. 127(6): p. 1952-1959.
4.Samet, J.M., et al., Fine particulate air pollution and mortality in 20 U.S. cities, 1987-1994. N Engl J Med, 2000. 343(24): p. 1742-9.
5.Colais, P., et al., Particulate air pollution and hospital admissions for cardiac diseases in potentially sensitive subgroups. Epidemiology, 2012. 23(3): p. 473-81.
6.Gauderman, W.J., et al., The effect of air pollution on lung development from 10 to 18 years of age. N Engl J Med, 2004. 351(11): p. 1057-67.
7.Gehring, U., et al., Particulate matter composition and respiratory health: the PIAMA Birth Cohort study. Epidemiology, 2015. 26(3): p. 300-9.
8.Calderón-Garcidueña, L., et al., Air Pollution and Brain Damage. Toxicologic Pathology, 2002. 30(3): p. 373-389.
9.Ajmani, G.S., H.H. Suh, and J.M. Pinto, Effects of Ambient Air Pollution Exposure on Olfaction: A Review. Environ Health Perspect, 2016. 124(11): p. 1683-1693.
10.Doty, R.L., The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol, 2008. 63(1): p. 7-15.
11.Kim, S.H., et al., Rapid doubling of Alzheimer''s amyloid-beta40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution. F1000Res, 2012. 1: p. 70.
12.Block, M.L. and L. Calderon-Garciduenas, Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci, 2009. 32(9): p. 506-16.
13.Wu, Y.C., et al., Association between air pollutants and dementia risk in the elderly. Alzheimers Dement (Amst), 2015. 1(2): p. 220-8.
14.Guerra, R., et al., Exposure to inhaled particulate matter activates early markers of oxidative stress, inflammation and unfolded protein response in rat striatum. Toxicol Lett, 2013. 222(2): p. 146-54.
15.Levesque, S., et al., Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. Environ Health Perspect, 2011. 119(8): p. 1149-55.
16.Hartz, A.M., et al., Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier. FASEB J, 2008. 22(8): p. 2723-33.
17.Mumaw, C.L., et al., Microglial priming through the lung-brain axis: the role of air pollution-induced circulating factors. FASEB J, 2016. 30(5): p. 1880-91.
18.Choi, Y.S., et al., Fucoidan Extracted from Hijiki Protects Brain Microvessel Endothelial Cells Against Diesel Exhaust Particle Exposure-Induced Disruption. J Med Food, 2016. 19(5): p. 466-71.
19.Cheng, H., et al., Urban traffic-derived nanoparticulate matter reduces neurite outgrowth via TNFalpha in vitro. J Neuroinflammation, 2016. 13: p. 19.
20.Wang, Y., L. Xiong, and M. Tang, Toxicity of inhaled particulate matter on the central nervous system: neuroinflammation, neuropsychological effects and neurodegenerative disease. J Appl Toxicol, 2017. 37(6): p. 644-667.
21.Calderon-Garciduenas, L., et al., Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol, 2008. 36(2): p. 289-310.
22.Yokota, S., et al., Nasal instillation of nanoparticle-rich diesel exhaust particles slightly affects emotional behavior and learning capability in rats. The Journal of Toxicological Sciences, 2011. 36(3): p. 267-276.
23.Win-Shwe, T.T., et al., Spatial learning and memory function-related gene expression in the hippocampus of mouse exposed to nanoparticle-rich diesel exhaust. Neurotoxicology, 2008. 29(6): p. 940-7.
24.Selkoe, D.J., Alzheimer''s disease: Genes, proteins, and therapy. Physiological Reviews, 2001. 81(2): p. 741-766.
25.Jung, C.R., Y.T. Lin, and B.F. Hwang, Ozone, particulate matter, and newly diagnosed Alzheimer''s disease: a population-based cohort study in Taiwan. J Alzheimers Dis, 2015. 44(2): p. 573-84.
26.Bhatt, D.P., et al., A pilot study to assess effects of long-term inhalation of airborne particulate matter on early Alzheimer-like changes in the mouse brain. PLoS One, 2015. 10(5): p. e0127102.
27.Calderon-Garciduenas, L., et al., Brain inflammation and Alzheimer''s-like pathology in individuals exposed to severe air pollution. Toxicol Pathol, 2004. 32(6): p. 650-8.
28.Calderon-Garciduenas, L., et al., Early Alzheimer''s and Parkinson''s disease pathology in urban children: Friend versus Foe responses--it is time to face the evidence. Biomed Res Int, 2013. 2013: p. 161687.
29.Calderon-Garciduenas, L., et al., Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. J Alzheimers Dis, 2012. 28(1): p. 93-107.
30.Fagundes, L.S., et al., Direct contact with particulate matter increases oxidative stress in different brain structures. Inhal Toxicol, 2015. 27(10): p. 462-7.
31.Moulton, P.V. and W. Yang, Air pollution, oxidative stress, and Alzheimer''s disease. J Environ Public Health, 2012. 2012: p. 472751.
32.Poon, H.F., et al., Free radicals and brain aging. Clin Geriatr Med, 2004. 20(2): p. 329-59.
33.Veronesi, B., et al., Effects of subchronic exposures to concentrated ambient particles. VII. Degeneration of dopaminergic neurons in Apo E-/- mice. Inhal Toxicol, 2005. 17(4-5): p. 235-41.
34.Wang, J., et al., Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer''s disease. J Neurochem, 2005. 93(4): p. 953-62.
35.Floyd, R.A., et al., Hydroxyl free radical adduct of deoxyguanosine: sensitive detection and mechanisms of formation. Free Radic Res Commun, 1986. 1(3): p. 163-72.
36.Toyokuni, S., et al., Quantitative immunohistochemical determination of 8-hydroxy-2''-deoxyguanosine by a monoclonal antibody N45.1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model. Lab Invest, 1997. 76(3): p. 365-74.
37.Tran, M.H., et al., Amyloid beta-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. Faseb Journal, 2001. 15(6): p. 1407-+.
38.Yermilov, V., et al., Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro. Carcinogenesis, 1995. 16(9): p. 2045-50.
39.Inoue, S. and S. Kawanishi, Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett, 1995. 371(1): p. 86-8.
40.Oddo, S., et al., Triple-Transgenic Model of Alzheimer''s Disease with Plaques and Tangles. Neuron, 2003. 39(3): p. 409-421.
41.Nilsberth, C., et al., The ''Arctic'' APP mutation (E693G) causes Alzheimer''s disease by enhanced Abeta protofibril formation. Nat Neurosci, 2001. 4(9): p. 887-93.
42.Ancolio, K., et al., Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer''s disease. Proc Natl Acad Sci U S A, 1999. 96(7): p. 4119-24.
43.Scheuner, D., et al., Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer''s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer''s disease. Nature Medicine, 1996. 2(8): p. 864-870.
44.Johnston, J.A., et al., Increased beta-amyloid release and levels of amyloid precursor protein (APP) in fibroblast cell lines from family members with the Swedish Alzheimer''s disease APP670/671 mutation. FEBS Lett, 1994. 354(3): p. 274-8.
45.Citron, M., et al., Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci U S A, 1994. 91(25): p. 11993-7.
46.Cai, X.D., T.E. Golde, and S.G. Younkin, Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science, 1993. 259(5094): p. 514-6.
47.Citron, M., et al., Mutation of the beta-amyloid precursor protein in familial Alzheimer''s disease increases beta-protein production. Nature, 1992. 360(6405): p. 672-4.
48.Murayama, O., et al., Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer''s disease. Neurosci Lett, 1999. 265(1): p. 61-3.
49.Barghorn, S., et al., Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry, 2000. 39(38): p. 11714-21.
50.Janelsins, M.C., et al., Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer''s disease mice. Journal of Neuroinflammation, 2005. 2.
51.Kitazawa, M., et al., Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer''s disease. J Neurosci, 2005. 25(39): p. 8843-53.
52.Janelsins, M.C., et al., Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol, 2008. 173(6): p. 1768-82.
53.Olabarria, M., et al., Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer''s disease. Glia, 2010. 58(7): p. 831-8.
54.Billings, L.M., et al., Intraneuronal Abeta causes the onset of early Alzheimer''s disease-related cognitive deficits in transgenic mice. Neuron, 2005. 45(5): p. 675-88.
55.Stover, K.R., et al., Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer''s disease. Behav Brain Res, 2015. 289: p. 29-38.
56.Gimenez-Llort, L., et al., Modeling behavioral and neuronal symptoms of Alzheimer''s disease in mice: a role for intraneuronal amyloid. Neurosci Biobehav Rev, 2007. 31(1): p. 125-47.
57.Yan, Y.H., et al., Subchronic effects of inhaled ambient particulate matter on glucose homeostasis and target organ damage in a type 1 diabetic rat model. Toxicol Appl Pharmacol, 2014. 281(2): p. 211-20.
58.Li, C.S., et al., Analysis of oxidative DNA damage 8-hydroxy-2 ''-deoxyguanosine as a biomarker of exposures to persistent pollutants for marine mammals. Environmental Science & Technology, 2005. 39(8): p. 2455-2460.
59.Guindon, K.A., L.L. Bedard, and T.E. Massey, Elevation of 8-hydroxydeoxyguanosine in DNA from isolated mouse lung cells following in vivo treatment with aflatoxin B1. Toxicol Sci, 2007. 98(1): p. 57-62.
60.European Standards Committee on Oxidative, D.N.A.D., Measurement of DNA oxidation in human cells by chromatographic and enzymic methods. Free Radic Biol Med, 2003. 34(8): p. 1089-99.
61.Wu, K.Y., et al., A gas chromatography/electron capture/negative chemical ionization high-resolution mass spectrometry method for analysis of endogenous and exogenous N7-(2-hydroxyethyl)guanine in rodents and its potential for human biological monitoring. Chem Res Toxicol, 1999. 12(8): p. 722-9.
62.Yermilov, V., J. Rubio, and H. Ohshima, Formation of 8-nitroguanine in DNA treated with peroxynitrite in vitro and its rapid removal from DNA by depurination. FEBS Lett, 1995. 376(3): p. 207-10.
63.Hsieh, Y.S., et al., Formation of 8-nitroguanine in tobacco cigarette smokers and in tobacco smoke-exposed Wistar rats. Chem Biol Interact, 2002. 140(1): p. 67-80.
64.Quang, T.N., et al., Vertical particle concentration profiles around urban office buildings. Atmospheric Chemistry and Physics, 2012. 12(11): p. 5017-5030.
65.Clinton, L.K., et al., Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol Dis, 2007. 28(1): p. 76-82.
66.Floyd, R.A. and J.M. Carney, Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann Neurol, 1992. 32 Suppl: p. S22-7.
67.Floyd, R.A., Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med, 1999. 222(3): p. 236-45.
68.Stadtman, E.R. and B.S. Berlett, Reactive oxygen-mediated protein oxidation in aging and disease. Chem Res Toxicol, 1997. 10(5): p. 485-94.
69.Sohal, R.S., R.J. Mockett, and W.C. Orr, Mechanisms of aging: an appraisal of the oxidative stress hypothesis1,2 1This article is part of a series of reviews on “Oxidative Stress and Aging.” The full list of papers may be found on the homepage of the journal. 2Guest Editor: Rajindar S. Sohal. Free Radical Biology and Medicine, 2002. 33(5): p. 575-586.
70.Zhang, J., et al., Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science, 1994. 263(5147): p. 687-9.
71.Wang, J., W.R. Markesbery, and M.A. Lovell, Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment. J Neurochem, 2006. 96(3): p. 825-32.
72.Mecocci, P., U. MacGarvey, and M.F. Beal, Oxidative damage to mitochondrial DNA is increased in Alzheimer''s disease. Ann Neurol, 1994. 36(5): p. 747-51.
73.Butterfield, D.A., et al., Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer''s disease and mild cognitive impairment. Free Radic Biol Med, 2007. 43(5): p. 658-77.
74.Behl, C., et al., Hydrogen-Peroxide Mediates Amyloid-Beta Protein Toxicity. Cell, 1994. 77(6): p. 817-827.
75.Hensley, K., et al., A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci U S A, 1994. 91(8): p. 3270-4.
76.Yan, S.D., et al., Non-enzymatically glycated tau in Alzheimer''s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med, 1995. 1(7): p. 693-9.
77.Misonou, H., M. Morishima-Kawashima, and Y. Ihara, Oxidative stress induces intracellular accumulation of amyloid beta-protein (A beta) in human neuroblastoma cells. Biochemistry, 2000. 39(23): p. 6951-6959.
78.Cardozo-Pelaez, F., et al., Oxidative DNA damage in the aging mouse brain. Mov Disord, 1999. 14(6): p. 972-80.
79.Oddo, S., et al., A Dynamic Relationship between Intracellular and Extracellular Pools of Aβ. The American Journal of Pathology, 2006. 168(1): p. 184-194.
80.Faghihi, M.A., et al., Expression of a noncoding RNA is elevated in Alzheimer''s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med, 2008. 14(7): p. 723-30.
81.Fonken, L.K., et al., Air pollution impairs cognition, provokes depressive-like behaviors and alters hippocampal cytokine expression and morphology. Mol Psychiatry, 2011. 16(10): p. 987-95, 973.
82.Janus, C., et al., A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer''s disease. Nature, 2000. 408(6815): p. 979-82.
83.Morgan, D., et al., A beta peptide vaccination prevents memory loss in an animal model of Alzheimer''s disease. Nature, 2000. 408(6815): p. 982-5.
84.Dodart, J.C., et al., Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer''s disease model. Nat Neurosci, 2002. 5(5): p. 452-7.
85.Piao, F., et al., Abnormal expression of 8-nitroguanine in the brain of mice exposed to arsenic subchronically. Ind Health, 2011. 49(2): p. 151-7.
86.Hernandez, F. and J. Avila, Intra- and extracellular protein interactions with tau. Curr Alzheimer Res, 2010. 7(8): p. 670-6.
87.Llorens-Martin, M., et al., GSK-3beta, a pivotal kinase in Alzheimer disease. Front Mol Neurosci, 2014. 7: p. 46.
88.Oddo, S., et al., Genetically altering Abeta distribution from the brain to the vasculature ameliorates tau pathology. Brain Pathol, 2009. 19(3): p. 421-30.
89.Guo, J.P., et al., Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer''s disease. Proc Natl Acad Sci U S A, 2006. 103(6): p. 1953-8.
90.Bolmont, T., et al., Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci, 2008. 28(16): p. 4283-92.
91.Simard, A.R., et al., Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer''s disease. Neuron, 2006. 49(4): p. 489-502.
92.Malm, T.M., et al., Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis, 2005. 18(1): p. 134-42.
93.Iwata, N., et al., Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med, 2000. 6(2): p. 143-50.
94.Eckman, E.A., D.K. Reed, and C.B. Eckman, Degradation of the Alzheimer''s amyloid beta peptide by endothelin-converting enzyme. J Biol Chem, 2001. 276(27): p. 24540-8.
95.Qiu, W.Q., et al., Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem, 1998. 273(49): p. 32730-8.
96.Hu, J., et al., Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem, 2001. 276(51): p. 47863-8.
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